There is a great need in biomedical applications, including orthopedic practice, for sealants or adhesives of wounds and surgical cuts. Such sealants contemplated could range from sealants used for wound healing and wound closure on the skin to sealants used to permanently seal scalpel cuts and puncture wounds made by large bore injection needles in the course of various procedures.
At present, there is no satisfactory orthopedic sealant being used to satisfy the need for closing iatrogenic defects made in the annulus fibrosa during discectomies. This can cause serious problems in that the intervertebral disc may subsequently undergo accelerated degeneration, and the patient may require a spinal fusion some years later. Some implants have been proposed to resolve the issue but these were introduced without biomechanical considerations. Mechanical barriers have been recently proposed but are fundamentally different from an annulus sealant in that it (1) lacks the ability to reconstruct the annulus directly and restore motion, (2) cannot prevent the leakage of smaller particles from within the nucleus pulposus, (3) is more technically difficult to employ, and (4) would carry a significant risk of neurologic injury if extruded into the canal. No long term data is available on these products.
Further, there is also an unmet need for more flexible wound closure adhesives on the surface of the skin. Currently known wound closure adhesives include 2-octyl-cyanoacrylate (Oct-CA), known commercially by the brand name Dermabond®, available from Ethicon US LLC, a Johnson & Johnson company, wherein Dermabond® is a registered trademark of Johnson & Johnson Company, New Brunswick, N.J., and N-butyl-2-cyanoacrylate, known commercially by either Indermil® tissue adhesive, available from Covidien Co., a Henkel company, wherein Indermil® is a registered trademark of Henkel Corporation, Rocky Hill, Conn., or Histoacryl® topical skin adhesive, available from B. Braun Corporation, wherein Histoacryl® is a registered trademark of Aesculap, Inc., Center Valley, Pa. That is, it is well known that these monomers readily polymerize upon exposure to traces of moisture on surfaces such as skin. The CA group in these compounds is highly reactive toward nucleophiles because of the presence of the two highly electron withdrawing substituents (CN— and COO—), so that CA polymerizations are initiated by moisture. For instance, lower alkyl CAs such as methyl cyanoacrylates or ethyl cyanoacrylate (Superglue®) instantaneously polymerize in the presence of surface moisture. The rates of polymerizations are notably lower with the higher alkyl CAs (e.g., Oct-CA) due to the lower molar concentration of the CA groups.
Accordingly, a need exists to increase the rate of polymerization of these higher alkyl CAs (e.g., Oct-CA) without introducing any lower alkyl CAs, since the lower alkyl CAs are known to have toxicity concerns and cannot be used inside the body, but yet provide increase flexibility upon polymerization and higher viscosity than is normally available using commercially available wound closures containing 2-octyl-cyanoacrylate (Oct-CA) as the active ingredient. That is, commercial products such as Dermabond® are known to exhibit undesirably low viscosity (i.e., too runny) and to exhibit undesirable stiffness upon production (i.e., the coatings produced are too stiff and have low tensile strength).
More recently, and to overcome at least the stiffness problem, homopolymer networks containing cyanoacrylate-functionalized multi-arm polyisobutylene stars have been employed to provide more flexibility and rubberyness. These homopolymer networks have been developed and patented. The production of such polyisobutylenes provide for a core (Ø) with a desired number of polyisobutylene arms extending therefrom.
There are many potential biomedical applications with polyisobutylene with attachment of various polymers at the end of each arm. One clinical example where polyisobutylene has been adopted is poly(styrene-b-isobutylene-b-styrene), which is currently used as a coating in the Taxus® Drug Eluting Stent. Another potential application is for all applications where 2-octyl cyanoacrylate (Dermabond®) is currently employed and more flexibility is required.
To that end, cyanoacrylate-telechelic three-arm star polyisobutylenes have been prepared. Cyanoacrylate-telechelic three-arm star polyisobutylenes, Ø(PIB-CA)3, were first prepared in 1991. A low viscosity syringible and injectable homopolymer functionalized with ethyl cyanoacrylate (i.e., Et-CA) was subsequently developed in 2007. It was found that a bolus of covalently linked PIB rubber “superglue” was created when Ø(PIB-CA)3 was injected into (egg) protein and the properties could be controlled by addition of polyethyl-2-cyanoacrylate. On its own, Ø(PIB-CA)3 has a tensile strength of 1.6 MPa, Young's Modulus of 4.9 MPa, and an elongation of 70%. Comparatively, the tensile strength of clinically available 2-octyl cyanoacrylate based “superglue”, Dermabond® (Ethicon, J&J) and SurgiSeal™ (Adhezion Biomedical), is less than 0.1 MPa.
Furthermore, it was found that cyanoacrylate-ended tri-telechelic polyisobutylene Ø(PIB-CA)3 (Mn˜2500 g/mol or more) are nontoxic in rats in vivo. Without being bound by theory, it is believed that the biocompatible high barrier rubbery PIB moiety effectively envelops and shields the noxious cyanoacrylate groups from the surrounding tissue and the permanently sequestered -CA groups are rendered harmless. However, too high molecular weight Ø(PIB-CA)3 could also render the benefit of the —CA groups useless as well, as the rate of polymerization would be greatly slowed.
As noted above, it took several years for the production of a co-network of Ø(PIB-CA)3 and Et-CA. This is because Et-CA is not miscible with Ø(PIB-CA)3. It was only by way of mechanical means (i.e., a dual injectable syringe) that the two components could be brought into contact with each other at a particular site for use. Moreover, the amount and molecular weight of Et-CA was such that only small amounts could be used. Accordingly, the result was the production of a homopolymer network wherein the Et-CA was considered simply a crosslinker. That is, the molar ratio of the Ø(PIB-CA)3 to Et-CA was so high that the resultant product is today considered a network with a Et-CA crosslinker, rather than a co-network of Ø(PIB-CA)3 and Et-CA. Thus, other alternative networks to Ø(PIB-CA)3 and Et-CA were sought.
Even more recently, new co-networks consisting of Ø(PIB-CA)3 and Oct-CA have been developed. Such co-networks have been found to provide the flexibility, elongation and tensile strength of Ø(PIB-CA)3 with the “superglue” properties of 2-octyl cyanoacrylates. The polymerization of simple alkyl cyanoacrylates, and specifically, 2-octyl cyanoacrylate (Oct-CA), with and in addition to the cyanoacrylate-functionalized three arm star polyisobutylenes, Ø(PIB-CA)3, have been found to provide useful co-networks that may be desirable in a number of biomedical applications.
However, heretofore, the co-networks, have only been tested on moisture-provided surfaces such as skin. As such, known co-networks of poly(2-octyl cyanoacrylate) (Oct-CA) and tri-telechelic cyanoacrylate-functionalized polyisobutylene (Ø(PIB-CA)3) have only been developed by way of initiation from moisture obtained from the surface to which it is applied. That is, the polymerization reaction was initiated by nucleophilic groups located on the surface to be covered by the co-network, such as, in one embodiment, skin. The co-network exhibited higher elongation than a homopolymer of octyl cyanoacrylate and exhibited strength sufficient to hold two pieces of skin together. However, when using only the skin or moisture from the surface covered as an initiator, the set time of the adhesive, i.e., the time the liquid wound closure adhesive (i.e., the co-network) takes to become a tack free solid after applying it to surfaces, is somewhat lengthy (i.e., much longer than 120 seconds—typically 6 to 10 minutes) compared to the set times preferred by doctors who would use the wound closure adhesives. Such preferred set times are in the 30-120 seconds range. Again, without being bound by theory, it is believed that the rate of polymerization is slowed due to the initiation of the polymerization via only the nucleophiles on the skin.
Therefore, the need exists for other co-networks formed by polymerizing tri-telechelic cyanoacrylate-functionalized polyisobutylene (Ø(PIB-CA)3) and 2-octyl cyanoacrylate (Oct-CA) that are initiated, or rather, super initiated by methods other than from moisture on the surface to which they are being applied. While it may be possible or desirable to enhance the initiation process with the nucleophilic groups located on the surface (e.g, skin) covered by the poly co-network, the present invention seeks to use other initiation methods and other initiators, including novel initiators to provide improved co-networks of tri-telechelic cyanoacrylate-functionalized polyisobutylene (Ø(PIB-CA)3) and 2-octyl cyanoacrylate (Oct-CA) for use in various biomedical applications such as wound closure adhesives.
One known initiator is N,N-dimethyl-p-toluidine (DMT), commercially available from Aldrich. DMT was used to initiate the polymerization of Ø(PIB-CA)3 with ethyl cyanoacrylate to form the co-network. In practice, approximately 0.8 grams of Ø(PIB-CA)3 was dissolved in 3 mL toluene, as a solvent, in a 10 mL test tube, and small amounts of Et-CA were added, followed by 1 drop (approximately 37 μmol) of DMT initiator. The solution was shaken and then poured into a 5×5 cm square Teflon mold, covered with aluminum foil, and the solvent was then evaporated in a fume hood for 2 days. Finally, the film was vacuum dried at 100° C. to constant weight and sol fractions were determined in THF.
To date, the use of DMT has been limited to initiation of Ø(PIB-CA)3 with ethyl cyanoacrylate as a crosslinker. It has not been used to date in a physical co-network like the present invention. Even so, the need exists for new initiators (a) that do not require solvents, (b) that can be used for the polymerization of tri-telechelic cyanoacrylate-functionalized polyisobutylene (Ø(PIB-CA)3) and 2-octyl cyanoacrylate (Oct-CA), and/or (c) that provide improvements in the mechanical properties.
Again, for skin, the active ingredient in commercially successful wound closure adhesives are alkyl cyanoacrylates (CAs), typically, butyl- or 2-octyl cyanoacrylate (Bu-CA, Oct-CA), marketed under a variety of trade names, such as Hystoacryl® and Dermabond®, respectively. The CA molecules, due to their strongly electron-withdrawing groups at unsaturations, rapidly polymerize upon contact with even the weakest of nucleophiles, such as water. Thus, the moisture on the skin may be sufficient in some cases to provide for the polymerization. However, that is not true for all cases.
Wound closure adhesives are usually packaged in special delivery devices, wherein the CA (together with a variety of additives, modifying agents, etc.) is sealed in a thin-walled glass vial that is crushed upon deployment, and the liquid monomer is forced toward the skin through a small porous plastic sponge (typically of polypropylene) situated at the tip of the delivery port.
It is not generally appreciated that this sponge performs two critical functions: (a) it helps delivering the active ingredient evenly over the targeted surface, and, more importantly, (b) it contains a key component, the initiator, which induces and accelerates the polymerization of the CA monomer as it is squeezed through the sponge. Absent the initiator, the set time is undesirably long, usually many minutes (i.e. 6 to 10 minutes).
The scientific literature mentions a large variety of initiators for the polymerization of alkyl CAs, e.g., water, bases, anions, methanol, amines, phosphines, and alkyl ammonium salts. However, the exact nature and concentrations of initiators used in commercial devices are closely guarded trade secrets. A search of the patent literature gave some insight as to the identity of initiators employed in practice for the polymerization of CAs in general and Oct-CA in particular, together with the nature of other ingredients (plasticizing agents, stabilizers, thickeners, etc.) dissolved in Oct-CA for commercial formulations to enhance the performance of these adhesives. However, it is readily apparent that the initiator of choice most often used to rapidly polymerize CAs, especially Oct-CA is DMT.